Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents

Summary

This protocol describes the use of amide coupling reactions of isonicotinic acid and diaminoalkanes to form bridging ligands suitable for use in the synthesis of multinuclear platinum complexes, which combine aspects of the anticancer drugs BBR3464 and picoplatin.

Abstract

Amide coupling reactions can be used to synthesize bispyridine-based ligands for use as bridging linkers in multinuclear platinum anticancer drugs. Isonicotinic acid, or its derivatives, are coupled to variable length diaminoalkane chains under an inert atmosphere in anhydrous DMF or DMSO with the use of a weak base, triethylamine, and a coupling agent, 1-propylphosphonic anhydride. The products precipitate from solution upon formation or can be precipitated by the addition of water. If desired, the ligands can be further purified by recrystallization from hot water. Dinuclear platinum complex synthesis using the bispyridine ligands is done in hot water using transplatin. The most informative of the chemical characterization techniques to determine the structure and gross purity of both the bispyridine ligands and the final platinum complexes is ¹H NMR with particular analysis of the aromatic region of the spectra (7-9 ppm). The platinum complexes have potential application as anticancer agents and the synthesis method can be modified to produce trinuclear and other multinuclear complexes with different hydrogen bonding functionality in the bridging ligand.

Introduction

Platinum anticancer drugs remain one of the most widely used family of agents in the treatment of human cancer¹. Despite their success, they are limited in their application by severe dose-limiting side effects^2-4. The limited doses that can be administered to patients also means that tumors can develop resistance⁵. As such, new drugs continue to be developed to improve the side effect profile and overcome acquired resistance, like phenanthriplatin⁶ and phosphaplatin⁷.

In the late 1990s, a trinuclear platinum drug was developed, BBR3464 (Scheme 1)⁸, that is u....

Protocol

1. Synthesis of the N,N’-(alkane-1,n-diyl)diisonicotinamide

1. Dry a single neck or three-neck round bottom flask in an oven (100 ºC, 1 hr) to ensure all moisture is removed.
2. Add solid isonicotinic acid, or its derivative, to the flask along with a magnetic stirring bar. If the diaminoalkane ligand(s) are solids at room temperature, then 0.5 mole (to the number moles of isonicotinic acid) is added to the flask at this stage.
3. Cap the neck(s) of the flask with rubber septa and replace the air in the flask with nitrogen either through a continuous nitrogen stream or through the use of nitrogen filled balloons.
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Results

The bispyridine ligands and their respective dinuclear platinum complexes are characterized by ¹H, ¹³C and ¹⁹⁵Pt NMR (Tables 1 and 2), and electrospray ionization mass spectroscopy. Accurate melting points can be determined using differential scanning calorimetry and purity is best determined by elemental analysis for C, H and N percentage content. Of most use is ¹H NMR as it is quick and easy to use, giving results within minutes of isolation .......

Discussion

In this work dinuclear platinum complexes have been synthesized as potential anticancer agents. In doing so bispyridine bridging ligands were synthesized via an amide coupling reaction using isonicotinic acid and variable length diaminoalkanes. Previously the synthesis of bispyridine ligands and their methyl analogues with 2 to 8 methylene groups and their respective platinum complexes have been reported. In this paper, the synthesis and purification method has been revised making it faster and cheaper and have demonstra.......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
D2O	Aldrich	151882	99.9% D
DMSO-d6	Aldrich	156914	99.96% D
1,8-diaminooctane	Aldrich	D22401	98%
1,10-diaminodecane	Aldrich	D14204	98%
1,12-diaminododecane	Aldrich	D1,640-1	98%
Isonicotinic acid	Aldrich	I17508	99%
1-Propylphosphonic anhydride solution	Aldrich	431303	50 wt% in ethyl acetate
Trans-diaminodichloridoplatinum(II)	Aldrich	P1525
Dimethylsulfoxide	Sigma-Aldrich	Z76855	>99.9%, anhydrous
N,N’-dimethylformamide	Sigma-Aldrich	227056	99.8%, anhydrous
Triethylamine	Sigma-Aldrich	T0886	>99%
Nylon filter membranes	Whatman	7402-004	Pore size, 0.2 µm
Magnetic stirring hotplate
Magnetic stirring bar
Round bottom or three neck flask
Rubber septums of sufficient size for chosen round bottom or three neck flask
5 ml hypodermic syringes
Hypodermic needles
Rubber party ballons
Rubber bands
A source of N2 gas
Rotary evaporator
Drying oven
NMR tubes
NMR spectrometer
500 ml beakers
Glass or plastic pipettes